Process for the preparation of ethers deriving from hydroxybenzoic acids

ABSTRACT

Process for the preparation of ethers of hydroxybenzoic acid having general formula (I), which comprises reacting a hydroxybenzoic acid, optionally substituted, with a halide XR1, wherein X is a halogen such as chlorine, in a basic environment and in an aqueous or aqueous/organic biphasic solvent.

The present invention relates to a process for the preparation of ethersderiving from hydroxybenzoic acids. These products are particularlyuseful as intermediates for pharmaceutical syntheses, in agrarianchemistry, in dyes, fragrances, pharmaceutical solutions for dentalcements and as adhesive components.

More specifically, the present invention relates to a process for theproduction of o-ethoxybenzoic acid (2-EBA) used in particular as anintermediate for pharmaceutical syntheses.

Preparation methods of ethers of hydroxybenzoic acids are known inliterature. For example, in Zh. Org. Khim., vol. 23, Nr. 3, pages667-668, the preparation is described of alkyl ethers of hydroxybenzoicacid starting from an aqueous solution of potassium hydroxide,containing o-hydroxybenzoic acid, and from an alkyl halide. Thereaction, catalyzed by crown-ethers, also produces high quantities ofether with the esterified carboxylic function. This ether-ester must betreated in a second phase to saponify the esterified function by meansof hydrolysis.

With the aim of overcoming this drawback, a synthesis method alternativeto the previous one was proposed in the patent U.S. Pat. No. 5,344,968,which comprises the reaction between a chlorobenzoic acid and a C₁-C₅alkyl alcohol in the presence of a catalytic system consisting of acopper salt and an alkyl amine. Although characterized by a betterselectivity, with respect to the method described above, the process ofpatent U.S. Pat. No. 5,344,968 still requires the use of a complexcatalytic system which, at the end of the reaction, must be separatedfrom the end-product.

U.S. Pat. No. 4,161,611 teaches the preparation of a methyl ether of2-hydroxy3,6-dichlorobenzoic acid with methyl chloride in water andsodium hydroxide, the pH being maintained during the reaction in therange of 10-12 by the periodic addition of NaOH.

The Applicant has now found that it is possible to obtain alkyl ethersof hydroxybenzoic acids in a single passage by reacting salicylic acidwith an alkyl chloride, in the presence of a base, without the formationof an ether-ester. More specifically, operating according to the processobject of the present invention, it is possible to obtain alkoxybenzoicacid directly with good yields and a high selectivity by reacting, inwater, an alkaline salt of salicylic acid with an alkyl chloride and analkaline base fed simultaneously but so as to maintain a slight excessof alkaline base in reaction, according to the following reactionscheme:

Operating according to this process, the following advantages areobtained with respect to the known art:

use of an economic reagent, such as alkyl chloride, which makes theprocess competitive also from an industrial point of view;

use of an economic and simple solvent such as water operating in asingle aqueous phase;

possibility of also carrying out the reaction in a mixedwater/non-miscible solvent (for example toluene) system, thus obtaininga reduction in the reaction pressure;

elimination of reaction by-products such as alkyl esters of etherifiedsalicylic acid, and the consequent elimination of subsequent hydrolysissteps of said ether-esters to obtain the corresponding ethers only.

An object of the present invention therefore relates to a process forthe preparation of ethers of hydroxybenzoic acid having general formula(I):

wherein R₁ represents a linear or branched C₁-C₆ alkyl group or analkylaromatic group wherein the alkyl group contains from 1 to 4 carbonatoms and wherein R₁ represents a hydrogen atom or a C₁-C₄ alkoxy,phenoxy, benzyloxy group, or a C₁-C₄ alkyl radical, a C₂-C₄ alkenylradical, a —COCH₃ or Y—CHO acetyl radical, wherein Y represents a simplebond or a C₁-C₄ alkyl radical, or it represents an —NO₂ or —NR₃R₄ groupwherein R₃R₄, the same or different, are selected from a hydrogen atomor a C₁-C₄ alkyl radical, which comprises reacting a hydroxybenzoicacid, optionally substituted, with an XR₁ halide, wherein X is a halogensuch as chlorine, in a basic environment and in an aqueous oraqueous/organic biphasic solvent.

According to the present invention, the preferred but non-limitingcompound is that having general formula (I), wherein R₁ is an ethylradical in ortho position with respect to the carboxylic group andwherein R₂ represents a hydrogen atom.

The synthesis reaction, which can be carried out by feeding the reagentseither in continuous or batchwise, but preferably in continuous, takesplace between the hydroxybenzoic acid optionally substituted, preferablysalicylic acid, and an alkyl halide, preferably ethyl chloride, in thepresence of a base in order to fix the halogen which is released duringthe reaction in aqueous solvent. The feeding of the reagents isgenerally carried out in continuous feeding the base in advance withrespect to the ethyl chloride.

Preferred bases are aqueous sodium or potassium hydroxides. Organicbases such as trialkylamines can also be used, which block thehydrochloric acid in the hydrochloride form of the amine. Sodiumhydroxide used with molar ratios alkyl halide/NaOH ranging from 1/1 to1/3, preferably equal to 1/5, is particularly preferred. The reaction iscarried out in an autoclave at a pressure ranging from 1 to 15 atm andat a temperature ranging from 80° C. to 160° C., preferably from 110° C.to 130° C.

To favour the conversion of the hydroxybenzoic acid, it is preferable touse an excess of alkyl halide with respect to the aromatic substrate.The molar ratios hydroxybenzoic acid/alkyl halide range from 1/1.5 to1/4, preferably from 1/2 to 1/2.5.

When the reaction solvent is water alone, this is used in such aquantity as to have a weight ratio hydroxybenzoic acid/water, at the endof the feeding, ranging from 1/2 to 1/6, preferably from 1/3 to 1/4.When the water is mixed with a non-miscible organic solvent, for exampletoluene or xylenes, the latter is present in a quantity ranging from 5to 50% by volume with respect to the total water+solvent volume.

Some illustrative but non-limiting examples are provided for a betterunderstanding of the present invention.

EXAMPLE 1

69.1 g (0.5 moles) of salicylic acid suspended in 83 g of demineralizedwater are salified with 69.1 g (0.52 moles) of NaOH at 30% in a 1 literopen autoclave. After closing the autoclave, 80.6 g (1.25 moles) ofethyl chloride and 192 g (1.44 moles) of NaOH at 30% are chargedseparately but simultaneously in 6 h under strict pressure control. Atthe end of the feeding, the mixture is left for 2 h at athermostat-regulated temperature (T=120° C.) until a stable pressureindication is obtained.

The reaction mixture at the end of the synthesis is acidified to pH1.5-2 with HCL 20% (126.3 g) and extracted with methylene chloride (130g).

After distillation of the solvent, 70.8 g (0.426 moles) of 2-EBA and 8.6g (0.062 moles) of non-reacted salicylic acid are recovered, equal to aconversion of 87.6% and a selectivity to 2-EBA of 97.2%.

EXAMPLE 2

The same procedure is adopted as described in example 1, adding, apartfrom water, an equal volume quantity of toluene (83 cm³) in theautoclave.

At the end of the synthesis, the reaction mixture consists of twoseparate phases, a toluene phase which is put aside and an aqueous phasewhich is acidified to pH 1.5-2 with HCl at 20% (120.8 g). This isextracted with toluene (55 g).

After distillation of the joined toluene phases, 71.0 g (0.43 moles) of2-ERA and 8.1 g (0.059 moles) of non-reacted salicylic acid arerecovered, equal to a conversion of 88.3% and a selectivity to 2-EBA of96.7%.

EXAMPLE 3

The same procedure is adopted as described in example 2, varying onlythe quantity of ethyl chloride used (114.5 g=1.775 moles) and thecorresponding NaOH (272 g=2.04 moles).

After distillation of the solvent, 73.1 g (0.44 moles) of 2-EBA and 6.35g (0.046 moles) of non-reacted salicylic acid are recovered, equal to aconversion of 90.8% and a selectivity to 2-EBA of 96.8%.

EXAMPLE 14

The same procedure is adopted as described in example 2, varying onlythe quantity of ethyl chloride used (71.0 g=1.10 moles) and thecorresponding NaOH (169 g=1.267 moles).

After distillation of the solvent, 63.7 g (0.383 moles) of 2-EBA and11.3 g (0.08 moles) of non-reacted salicylic acid are recovered, equalto a conversion of 83.6% and a selectivity to 2-EBA of 91.6%.

EXAMPLE 5

The same procedure is adopted as described in example 2, varying onlythe reaction temperature from 120° C. to 130° C.

After distillation of the solvent, 69.1 g (0.41 moles) of 2-ERA and 8.15g (0.059 moles) of non-reacted salicylic acid are recovered, equal to aconversion of 88.2% and a selectivity to 2-EBA of 94.2%.

EXAMPLE 6

The same procedure is adopted as described in example 2, varying onlythe reaction temperature from 120° C. to 100° C.

After distillation of the solvent, 60.4 g (0.36 moles) of 2-EBA and 13.6g (0.098 moles) of non-reacted salicylic acid are recovered, equal to aconversion of 80.3% and a selectivity to 2-EBA of 90.5%.

What is claimed is:
 1. A process for the preparation of one or moreethers of hydroxybenzoic acid of formula (I):

wherein R₁ represents a linear or branched C₁-C₈ alkyl group or analkylaromatic group wherein the alkyl group contains from 1 to 4 carbonatoms and wherein R₂ represents a hydrogen atom or a C₁-C₄ alkoxy,phenoxy, benzyloxy group, or a C₁-C₄ alkyl radical, a C₂-C₄ alkenylradical, a —COCH₃ or Y—CHO acetyl radical, wherein Y represents a singlebond or a C₁-C₄ alkyl radical, or it represents an —NO₂ or —NR₃R₄ groupwherein R₃ and R₄ may be the same or different, and are selected fromthe group consisting of a hydrogen atom or a C₁-C₄ alkyl radical, saidprocess comprising: reacting continuously at a pressure ranging from 0.1to 1.52 MPa, a hydroxybenzoic acid, optionally substituted, with an XR₁halide, wherein X is a halogen in a basic environment and in an aqueousor aqueous/organic biphasic solvent, in the presence of NaOH withreaction molar ratios alkyl halide/NaOH ranging from 1/1 to 1/3.
 2. Theprocess according to claim 1, wherein R₁ is an ethyl radical in orthoposition with respect to the carboxyl group and R₂ represents a hydrogenatom.
 3. The process according claim 1, wherein the reaction molarratios hydroxybenzoic acid/alkyl halide range from 1/1.5 to 1/4.
 4. Theprocess according to claim 1, wherein the reaction is carried out at atemperature ranging from 80° C. to 160° C.
 5. The process according toclaim 1, wherein the solvent is water and wherein the weight ratiohydroxybenzoic acid/water, when the reagents have been charged, rangesfrom 1/2 to 1.6.
 6. The process of claim 1, wherein the halogen ischlorine.